INHIBITION OF 2-AMINO-3-METHYLIMIDAZO[4,5-F] QUINOLINE-DNA ADDUCTS BYINDOLE-3-CARBINOL - DOSE-RESPONSE STUDIES IN THE RAT COLON

Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant cry pt foci and DNA adducts in rats given heterocyclic amine colon carcino gens, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), Mechanism studies indicate that I3C induces cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2), isozymes that respectively metabolize IQ via ring hydroxy lation or activate the carcinogen by N-hydroxylation, The present stud y examined the dose-response for induction of CYP1A1 versus CYP1A2 by I3C, and compared the profiles of induction with the dose-response for inhibition of IQ-DNA adducts in the colon of the F344 rat, Dietary eq uivalent doses of I3C in the range 100-1000 p.p.m. increased in a dose -related manner both ethoxyresorufin O-deethylase (EROD) and methoxyre sorufin O-demethylase (MROD) activities in the liver and colonic mucos a, and Western blots showed a corresponding induction of CYP1A1 and CY P1A2 proteins, However, dietary equivalent doses of I3C in the range 1 0-25 p.p.m. (i) reduced hepatic EROD and MROD activities and CYP1A pro tein levels compared with controls, (ii) increased the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to a more potent mutagen when l iver microsomes from rats given I3C were used for metabolic activation in the Salmonella assay, Rats given a single oral dose of I3C shortly before administering IQ (5 mg/kg body wt, p.o.) exhibited dose-relate d inhibition of colonic IQ-DNA adducts in the range 25-100 p.p.m. I3C, reaching 95% inhibition at doses greater than or equal to 100 p.p.m. I3C, but IQ-DNA adducts were elevated slightly at the lowest I3C dose as compared with the controls, The possible significance of the low ve rsus high dose effects of I3C are discussed in the context of human di etary exposures to I3C and the reported chemopreventive mechanisms of I3C in vivo.